Derivatives of 5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators

ABSTRACT

This invention provides compounds of formula I 
     
       
         
         
             
             
         
       
     
     where the dashed line represents an optional double bond;
 
where R 1  is phenyl, naphthyl, pyridyl, pyrimidyl, pyrrolyl, imidazolyl, pyrazyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, optionally substituted, and other substituents are defined herein. Such compounds are potassium channel modulators.

This application is a continuation of U.S. application Ser. No.12/189,709, filed Aug. 11, 2008, which claims priority under 35 U.S.C.§119(e) to U.S. Provisional Application No. 60/964,526, filed Aug. 13,2007, each of which the entire contents are incorporated herein byreference.

FIELD OF THE INVENTION

This invention concerns novel compounds that modulate potassiumchannels. The compounds are useful for the treatment and prevention ofdiseases and disorders which are affected by activities of potassium ionchannels. One such condition is seizure disorders.

BACKGROUND OF THE INVENTION

Epilepsy is a well-known neurological disease, found in about 3% of thepopulation. Approximately 30% of patients with epilepsy do not respondto currently available therapies. Retigabine(N-[2-amino-4-(4-fluorobenzylamino)phenyl]carbamic acid, ethyl ester](U.S. Pat. No. 5,384,330) has been found to be an effective treatment ofa broad range of models of seizure disorders, and it appears to have anunusual mechanism of action. Bialer, M. et al., Epilepsy Research 1999,34, 1-41; Wuttke, T. V., et al., Mol. Pharmacol. 2005, 67, 1009-1017.Retigabine has also been found to be useful in treating pain, includingneuropathic pain. Blackburn-Munro and Jensen, Eur. J. Pharmacol. 2003,460, 109-116; Wickenden, A. D. et al., Expert Opin. Ther. Patents, 2004,14 (4).

“Benign familial neonatal convulsions,” an inherited form of epilepsy,has been associated with mutations in the KCNQ2/3 channels. Biervert, C.et al., Science 1998, 27, 403-06; Singh, N. A., et al., Nat. Genet.1998, 18, 25-29; Charlier, C. et al., Nat. Genet. 1998, 18, 53-55;Rogawski, Trends in Neurosciences 2000, 23, 393-398. Subsequentinvestigations have established that one important site of action ofretigabine is the KCNQ2/3 channel. Wickenden, A. D. et al., Mol.Pharmacol. 2000, 58, 591-600; Main, M. J. et al., Mol. Pharmcol. 2000,58, 253-62. Retigabine has been shown to increase the conductance of thechannels at the resting membrane potential, with a possible mechanisminvolving binding of the activation gate of the KCNQ 2/3 channel.Wuttke, T. V., et al., Mol. Pharmacol. 2005, op.cit. With increasedsophistication of research in this area, retigabine has also been shownto increase neuronal M currents and to increase the channel openprobability of KCNQ 2/3 channels. Delmas, P. and Brown, D. A. Nat. RevsNeurosci., vol. 6, 2005, 850-62; Tatulian, L. and Brown, D. A., J.Physiol., (2003) 549, 57-63.

The most therapy-resistant type of seizure is the so-called “complexpartial seizure.” Retigabine has been found to be particularly potent inmodels for drug-refractory epilepsy. Retigabine is also active inseveral other seizure models. Because of retigabine's broad spectrum ofactivity and unusual molecular mechanism, there is hope that retigabinewill be effective in management of several seizure types, including thecomplex partial seizure, and in treatment of hitherto untreatable formsof epilepsy. Porter, Roger J., Nohria, Virinder, and Rundfeldt, Chris,Neurotherapeutics, 2007, vol. 4, 149-154.

The recognition of retigabine as a potassium channel modulator hasinspired a search for other—and, hopefully, better—potassium channelmodulators among compounds with structural features similar to those ofretigabine.

BRIEF DESCRIPTION OF THE INVENTION

In one embodiment, this invention provides a compound of formula I

where the dashed line represents an optional double bond; where R₁ isphenyl, naphthyl, pyridyl, pyrimidyl, pyrrolyl, imidazolyl, pyrazyl,furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl,optionally substituted with one or two substituents selectedindependently from halogen, C₁-C₆ alkyl, mono-halo C₁-C₆ alkyl, di-haloC₁-C₆ alkyl, CF₃, CN, S—C₁-C₆ alkyl, or O—C₁-C₆ alkyl; R₂ is H, methyl,or halogen; R₃ and R₄ are, independently, CF₃, OCF₃, OC₁-C₃ alkyl, haloor C₁-C₃ alkyl, where the C₁-C₃ alkyl groups are optionally substitutedwith one or more halogen atoms; X═O or S; Y is O or S; q=1 or 0; R₅ isC₁-C₆ alkyl where the C₁-C₆ alkyl alkyl group is optionally substitutedwith one or two groups selected, independently, from OH, OMe, OEt, F,CF₃, Cl, or CN; (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆cycloalkyl, CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl,CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ar₁,(CHR₆)_(w)Ar₁, CH₂(CHR₆)_(w)Ar₁, or (CHR₆)_(w)CH₂Ar₁, where w=0-3, Ar₁is phenyl, pyridyl, pyrrolyl, thienyl, or furyl, and R₆ is hydrogen,methyl, halogen, or methoxy; where all cyclic groups are optionallysubstituted with one or two substituents selected independently fromC₁-C₃ alkyl, halogen, OH, OMe, SMe, CN, CH₂F, and trifluoromethyl; or apharmaceutically acceptable salt thereof. Such compounds are potassiumchannel modulators.

In another embodiment, this invention provides a composition comprisinga pharmaceutically acceptable carrier and one or more of the following:a pharmaceutically effective amount of a compound of formula I; apharmaceutically effective amount of a pharmaceutically acceptable saltthereof; a pharmaceutically effective amount of a pharmaceuticallyacceptable ester thereof.

In yet another embodiment, this invention provides a method ofpreventing or treating a disease or disorder which is affected bymodulation of voltage-gated potassium channels, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of formula I or a salt or ester thereof.

In another embodiment, this invention provides or contemplates acomposition comprising a pharmaceutically acceptable carrier and atleast one of the following: i) a pharmaceutically effective amount of acompound of formula I; ii) a pharmaceutically acceptable salt thereof;iii) a pharmaceutically acceptable ester thereof; iv) a pharmaceuticallyacceptable solvate thereof.

In another embodiment, this invention provides or contemplates a methodof treating or preventing a disease or disorder which is affected byenhancement of neural M currents comprising administering to a patientin need thereof one or more of the following: i) a pharmaceuticallyeffective amount of a compound of formula I; ii) a pharmaceuticallyacceptable salt thereof; iii) a pharmaceutically acceptable esterthereof; iv) and a pharmaceutically acceptable solvate thereof.

In yet another embodiment, this invention provides a method ofpreventing or treating a disease or disorder which is affected byactivation of voltage-gated potassium channels, comprising administeringto a patient in need thereof one or more of the following: apharmaceutically effective amount of a compound of formula I; ii) apharmaceutically acceptable salt thereof; iii) a pharmaceuticallyacceptable ester thereof; and iv) a pharmaceutically acceptable solvatethereof.

In yet another embodiment, this invention provides or contemplates amethod of treating or preventing a seizure disorder in a humancomprising administering to a patient afflicted or potentially afflictedwith such disorder one or more of the following: a pharmaceuticallyeffective amount of a compound of formula I; ii) a pharmaceuticallyacceptable salt thereof; iii) a pharmaceutically acceptable esterthereof; iv) and a pharmaceutically acceptable solvate thereof.

In another embodiment, this invention provides or contemplates apharmaceutical formulation for oral administration comprising atherapeutically effective amount of a compound of formula I and eitheran appropriate tabletting agent or an appropriate syrup for pediatricuse.

In another embodiment, this invention provides or contemplates a tabletfor oral administration comprising a therapeutically effective amount ofa compound of formula I and an appropriate tabletting agent.

In another appropriate embodiment, this invention provides orcontemplates a syrup for pediatric use comprising a solution ordispersion or suspension of a compound of formula I and an appropriatesyrup.

In another embodiment, this invention contemplates a pharmaceuticalformulation for administration to animals, including companion animals(dogs and cats), and livestock comprising a therapeutically effectiveamount of a compound of formula I and a veterinary acceptable carrier.

In another embodiment, this invention contemplates a method ofpreventing or treating a disease or disorder which is affected byactivation of voltage-gated potassium channels comprising administeringto an animal in need thereof one or more of the following: i) apharmaceutically effective amount of a compound of formula I; ii) apharmaceutically acceptable salt thereof; iii) a pharmaceuticallyacceptable ester thereof; iv) and a pharmaceutically acceptable solvatethereof.

In another embodiment, this invention contemplates a method of treatinga seizure disorder in an animal comprising administering to an animalafflicted or potentially afflicted with such a disorder one or more ofthe following: i) a pharmaceutically effective amount of a compound offormula I; ii) a pharmaceutically acceptable salt thereof; iii) apharmaceutically acceptable ester thereof; iv) and a pharmaceuticallyacceptable solvate thereof.

This invention includes all tautomers, salts, and stereoisomeric formsof compounds of formula I. This invention also includes all compounds ofthis invention where one or more atoms are replaced by a radioactiveisotope thereof.

This invention provides or contemplates compounds of formula I abovewhere NH—C(═X)—(Y)_(q)—R₅ is each of the following: NHC(═O)R₅,NHC(═O)OR₅, NHC(═S)R₅, NHC(═S)SR₅, NHC(═S)OR₅, and NHC(═O)SR₅.

Thus, in one embodiment, this invention provides or contemplates acompound of formula I, where NH—C(═X)—(Y)_(q)—R₅ is NHC(═O)R₅.

In another embodiment, this invention provides or contemplates acompound of formula I, where NH—C(═X)—(Y)_(q)—R₅ is NHC(═S)R₅.

In another embodiment, this invention provides or contemplates acompound of formula I, where NH—C(═X)—(Y)_(q)—R₅ is NHC(═S)SR₅.

In another embodiment, this invention provides or contemplates acompound of formula I, where NH—C(═X)—(Y)_(q)—R₅ is each NHC(═O)OR₅.

In another embodiment, this invention provides or contemplates acompound of formula I, where NH—C(═X)—(Y)_(q)—R₅ is NHC(═S)OR₅.

In another embodiment, this invention provides or contemplates acompound of formula I, where NH—C(═X)—(Y)_(q)—R₅ is NHC(═O)SR₅.

In a more specific embodiment, this invention provides or contemplates acompound of formula I, where R₅ is C₁-C₆ alkyl, (CHR₆)_(w)C₃-C₆cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl, or CH₂(CHR₆)_(w)C₃-C₆cycloalkyl.

In a still more specific embodiment, this invention provides orcontemplates a compound of formula I, where R₅ is C₅-C₆ alkyl,(CH₂)_(w)C₅-C₆ cycloalkyl, or (CHR₆)_(w)CH₂C₅-C₆ cycloalkyl.

In another more specific embodiment, this invention provides orcontemplates a compound of formula I, where R₅ is C₅-C₆ alkyl,optionally substituted with one or two OH groups.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA below.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IB below.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IC below.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula ID below.

In another subgeneric embodiment, this invention provides orcontemplates a compound of formula IA, IB, IC, or ID, where R₃ and R₄are, independently, methyl, chloro, or methoxy.

In another, more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, IB, IC, or ID, where R₃ and R₄are both methyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, IB, IC, or ID, where R₁ isphenyl, substituted with halogen, cyano, CF₃, or methoxy, R₂ is H ormethyl, and R₅ is C₅-C₆ alkyl or CH₂—C₃-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, IB, IC, or ID, where R₁ issubstituted phenyl or unsubstituted phenyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, IB, IC, or ID, where R₁ isphenyl, substituted with halogen.

In a still more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, IB, IC, or ID, where R₁ isfluorophenyl, or difluorophenyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, IB, IC, or ID, where R₁ isphenyl, substituted with trifluoromethyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, IB, IC, or ID, where R₁ ishalophenyl, and R₅ is C₅-C₆ alkyl or CH₂—C₅-C₆ cycloalkyl.

In another more specific subgeneric embodiment, this invention providesor contemplates a compound of formula IA, IB, IC, or ID, where R₁ ishalophenyl and R₅ is CH₂—C₄-alkyl or CH₂—C₅— alkyl.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IA, IB, IC, or ID, where R₁ is halopyridyl.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IA or IC, where R₁ is dihalophenyl ordihalopyridyl; R₂ is H; and R₃ and R₄ are Cl, CF₃, or CH₃.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IB or ID, where R₁ is dihalophenyl ordihalopyridyl; R₂ is H; and R₃ and R₄ are Cl, CF₃, or CH₃.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IB or ID, where R₁ is halophenyl orhalopyridyl; R₂ is H; and R₃ and R₄ are Cl, CF₃, or CH₃.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IA or IC, where R₁ is3,5-dichlorophenyl or 3,5-difluorophenyl.

In another more specific embodiment, this invention provides orcontemplates a compound of formula IB or ID, where R₁ is3,5-dichlorophenyl or 3,5-difluorophenyl.

In another embodiment, this invention provides or contemplates acompound of formula I, in which R₅ is C₁-C₆ alkyl, where the C₁-C₆ alkylgroup is substituted with one or two groups selected, independently,from OH, OMe, OEt, F, CF₃, Cl, or CN.

In another embodiment, this invention provides or contemplates acompound of formula I, in which X is S, q is zero, R₁ is substitutedphenyl, R₂ is H, and R₅ is C₁-C₆ alkyl.

In another embodiment, this invention provides or contemplates acompound of formula I, in which X is S, q is zero, R₁ is substitutedphenyl, R₂ is H, and R₅ is C₁-C₆ alkyl.

In yet another embodiment, this invention provides or contemplates acompound of formula I, in which X is S, q is 1, Y is O, R₁ issubstituted phenyl, R₂ is H, and R₅ is C₁-C₆ alkyl.

In yet another embodiment, this invention provides or contemplates acompound of formula I, in which X is S, q is 1, Y is S, R₁ issubstituted phenyl, R₂ is H, and R₅ is C₁-C₆ alkyl.

DETAILED DESCRIPTION OF THE INVENTION

In designing compounds with therapeutic properties superior to those ofretigabine, shown below,

and in optimizing the desirable therapeutic properties of this compound,the present inventors have discovered that compounds of formula I havesurprising and exceptional activity toward potassium channels, asevidenced by potent activity, as measured in the rubidium (Rb+) effluxassay described below.

The inventors have further discovered that substitution at both the 2-and 6-positions of the central benzene ring confers a number ofdesirable properties, including both increased potency and increasedstability in vivo. Thus, 2,6-di-substitution is a critical feature ofsome embodiments of this invention.

The inventors have further discovered that, in particular, alkylsubstitution at both the 2- and 6-positions of the central benzene ringconfers desirable properties, including both increased potency andincreased stability in vivo. Thus, 2,6-dimethyl substitution is acritical feature of one embodiment of this invention.

Moreover, the inventors have also discovered that substitution withalkoxide groups at both the 2- and 6-positions of the central benzenering also confers a number of desirable properties, including bothincreased potency and increased stability in vivo. Thus, suchsubstitution is a critical feature of another embodiment of thisinvention.

Moreover, the inventors have also discovered that substitution at the 2-and 6-positions of the central benzene ring with substituents chosenfrom halogen, trifluoromethyl, and methoxy also confers a number ofdesirable properties, including both increased potency and increasedstability in vivo. Thus, such substitution is a critical feature of yetanother embodiment of this invention.

Among the embodiments of this invention, the most active compoundsdisplay a 40- to 400-fold improvement over retigabine, with the mostpromising compounds displaying EC₅₀s in the single-digit nanomolarrange. Activities of several compounds of this invention are shown inTable 1 below. The activity of retigabine is shown for comparativepurposes.

As used herein the term “potassium channel modulator” refers to acompound capable of causing an increase in potassium channel currents.It also refers to a compound capable of increasing the KCNQ2/3 channelopen probability. For preliminary testing of compounds for potassiumchannel modulating ability, the inventors have employed the rubidium ionefflux test described below.

As contemplated by this invention, compounds of formula I are designedfor oral or intravenous dosing of up to approximately 2000 mg per day.Thus, this invention contemplates solutions and suspensions of compoundsof formula I formulated for intravenous administration. Similarly,solutions and suspensions comprising a syrup such as sorbitol orpropylene glycol, among many other examples, in addition to compounds offormula I, suitable for oral pediatric administration, are alsocontemplated. Additionally, both chewable and non-chewable tabletscomprising compounds of formula I, along with pharmaceuticallyacceptable tabletting agents and other pharmaceutically acceptablecarriers and excipients, are also contemplated.

As used herein, the term “pharmaceutically acceptable carrier” comprisessuch excipients, binders, lubricants, tabletting agents anddisintegrants as are typically used in the art of formulation ofpharmaceuticals. Examples of such agents include—but are not limitedto—microcrystalline cellulose, lactose, starch, and dicalcium phosphate,and Providone. However, in view of the incompatibility of primary amineswith lactose, this invention does not contemplate compositions in whichactive ingredients with primary amine groups are combined with lactose.Additionally, disintegrants such as sodium starch glycolate, lubricantssuch as stearic acid and SiO₂, and solubility enhancers such ascyclodextrins, among many other examples for each group, arecontemplated. Such materials and the methods of using them are wellknown in the pharmaceutical art. Additional examples are provided inKibbe, Handbook of Pharmaceutical Excipients, London, PharmaceuticalPress, 2000.

The invention also contemplates pharmaceutical formulations foradministration to animals, comprising a therapeutically effective amountof a compound of formula I and a veterinary acceptable carrier. Anyanimal that is susceptible to seizure disorders is included within thescope of this invention.

Synthetic Procedures

Section I. Preparation of compounds of formula XIV is outlined in Scheme1.

Section II. Preparation of compounds of formula IX is outlined in Scheme2.

Section III. Preparation of compounds of formula XIX is outlined inScheme 3.

Section IV. Preparation of compounds of formula XX is outlined in Scheme4.

Section V. Preparation of compounds of formula XXI is outlined in Scheme5.

Section VI. Preparation of compounds of formula XXII is outlined inScheme 6.

Section VII. Preparation of compounds of formula XXIII is outlined inScheme 7.

Section VIII. Preparation of compounds of formula XXIV is outlined inScheme 8.

Section IX. Preparation of compounds of formula XXVI is outlined inScheme 9.

Section X. Preparation of compounds of formula XXVII is outlined inScheme 10.

4,6-Dimethyl-1H-indole-2-carboxylic acid ethyl ester (2)

In a flask fitted with a Dean-Stark trap, p-toluenesulfonic acidmonohydrate (132 g, 0.69 mol) in 500 ml of benzene was heated at refluxfor 2 hours. A solution of 3,5-dimethylphenylhydrazine hydrochloride(34.5 g, 0.2 mol), ethyl pyruvate (23.2 g, 0.2 mol), andp-toluenesulfonic acid monohydrate (0.85 g, 0.005 mol) in 500 ml ofbenzene, which had been refluxed for 2 hours with water removed througha Dean-Stark apparatus was then added. The resulting mixture was heatedat reflux and stirred overnight. After cooling, the solution was treatedwith saturated sodium bicarbonate solution and diluted with methylenechloride. The organic portion was washed twice with saturated sodiumbicarbonate solution, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by ISCO(hexane/EtOAc, 0-30%, 40 min) to give yellow solids, which wasrecrystallized from hexane/ethyl acetate (10%) to give colorless needles(35.6 g, 82%). ¹H NMR (DMSO-d₆, 400 MHz): δ 11.68 (brs, 1H, exchangeablewith D₂O, NH), 7.12 (s, 1H), 7.05 (s, 1H), 6.71 (s, 1H), 4.33 (q, J=6.8Hz, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 1.34 (t, J=6.8 Hz, 3H).

4,6-Dimethyl-1H-indole-2-carboxylic acid (3)

A mixture of 4,6-dimethyl-1H-indole-2-carboxylic acid ethyl ester (22 g,0.1 mol) and lithium hydroxide (4.8 g, 0.2 mol) in 400 ml of ethanol washeated at reflux overnight. The solvent was removed under reducedpressure and the residue was dissolved in water and neutralized with 10%HCl to pH<3. The resulting precipitates were filtered and washed withwater and dried in vacuo at 40° C. to give white solids (18 g, 95%). ¹HNMR (DMSO-d₆, 400 MHz): δ 12.73 (brs, 1H, exchangeable with D₂O, NH),11.55 (brs, 1H, exchangeable with D₂O, NH), 7.06 (s, 1H), 7.03 (s, 1H),6.69 (s, 1H), 2.44 (s, 3H), 2.35 (s, 3H).

4,6-Dimethyl-1H-indole (4)

Method A: A mixture of 4,6-dimethyl-1H-indole-2-carboxylic acid (3.61 g,19.09 mmol, 1 equiv), copper powder (850 mg, 13.36 mmol, 0.7 equiv), andfreshly distilled quinoline (50 mL) were brought at reflux for 2 h. Themixture was then cooled and filtered on Celite. The filtrate was pouredon ice, and the solution was brought to pH 4 with concentrated HCl andextracted with ethyl acetate (3×100 ml). The combined extracts werewashed with 2 N HCl (3×100 mL), saturated NaHCO₃, and brine. The organicsolution was dried over MgSO₄ and concentrated. The residue was flashchromatographed on silica gel using hexane-AcOEt (85-15) to give a whitesolid (2.6 g, 94%). ¹H NMR (DMSO-d₆, 400 MHz): δ 10.8 (brs, 1H,exchangeable with D₂O, NH), 7.19 (t, J=2 Hz, 1H), 6.99 (s, 1H), 6.62 (s,1H), 6.36 (t, J=2 Hz, 1H), 2.41 (s, 3H), 2.34 (s, 3H).

Method 2: This indole also was prepared heating 26 g (0.14 mol) of4,6-dimethyl-1H-indole-2-carboxylic acid to 230° C. for 3 hours. Aftercooling, the reactant was distilled under reduced pressure (2.9-4.4mmHg) at 130-135° C. to give a pure product as colorless oil (15.6 g,77%).

4,6-Dimethylindoline (5) and 1-Acetyl-4,6-dimethylindoline (6) areprepared by the following procedure.

4,6-Dimethylindole (1.08 g) was dissolved in acetic acid (20 ml), andsodium cyanoborohydride (2.3 g) was added portionwise at 15° C. Themixture was stirred at said temperature for one hour and poured into icewater. Saturated aqueous sodium bicarbonate was added to neutralize themixture and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine and dried over sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin benzene, and acetic anhydride (840 mg) was added, which was followedby stirring at room temperature for one hour. The reaction mixture waswashed with saturated aqueous sodium bicarbonate and saturated brine,and dried over sodium sulfate. The solvent was evaporated under reducedpressure. The residue was chromatographed (ISCO, hexane/EtOAc, 0-40%, 40min) to give 1.3 g of 1-acetyl-4,6-dimethylindoline.

¹H-NMR (CDCl₃) δ: 2.18 (6H, s), 2.30 (3H, s), 3.00 (2H, t, J=8.3 Hz),4.03 (2H, t, J=8.3 Hz), 6.66 (1H, s), 7.89 (1H, s).

1-Acetyl-4,6-dimethyl-5-nitroindoline (7) was prepared as follows.

1-Acetyl-4,6-dimethylindoline (2.6 g) was dissolved in acetic anhydride(35 ml), and nitric acid (d=1.5, 0.92 ml) dissolved in acetic anhydride(15 ml) was added dropwise at 0° C. The mixture was stirred at roomtemperature for one hour and poured into ice water. Saturated aqueoussodium bicarbonate was added to neutralize the mixture, and the mixturewas extracted with chloroform. The extract was washed with saturatedbrine and dried over sodium sulfate. The solvent was evaporated underreduced pressure. The residue was chromatographed (ISCO, hexane/EtOAc,0-40%, 40 min) to give 2.4 g of white solids. ¹H NMR (DMSO-d₆, 400 MHz):δ 6.95 (s, 1H), 4.19 (t, J=8.0 Hz, 2H), 3.04 (t, J=8.0 Hz, 2H), 2.26 (s,3H), 2.23 (s, 3H), 2.18 (s, 3H).

4,6-Dimethyl-5-nitroindoline (8) was prepared by the followingprocedure.

1-Acetyl-4,6-dimethyl-5-nitroindoline (2.4 g) was dissolved in methanol(25 ml). Hydrochloric acid 6N (20 ml) was added, followed by reflux for15 hours. After the completion of the reaction, the solvent wasevaporated under reduced pressure. The residue was dissolved inchloroform, and the mixture was washed with saturated aqueous sodiumbicarbonate and saturated brine, and dried over sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue waschromatographed (ISCO, hexane/EtOAc, 0-40%, 40 min) to give 1.8 g of4,6-dimethyl-5-nitroindoline as yellow solids. ¹H NMR (DMSO-d₆, 400MHz): δ 6.36 (brs, 1H, exchangeable with D₂O, NH), 6.20 (s, 1H), 3.54(t, J=8.0 Hz, 2H), 2.91 (t, J=8.0 Hz, 2H), 2.17 (s, 3H), 2.10 (s, 3H).

4,6-Dimethyl-5-nitro-1-(4-trifluoromethyl-benzyl)-indoline (9): R═CF₃

4,6-dimethyl-5-nitroindoline (0.33 g, 1.7 mmol) was dissolved indimethylformamide (10 ml), and sodium hydride (ca. 60% in oilsuspension, 136 mg) was added at 0° C. The mixture was stirred at 0° C.for 0.5 hour and 4-trifluoromethylbenzyl bromide (0.48 g, 2 mmol)) wasadded to the reaction mixture, which was followed by stifling at roomtemperature overnight. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine and dried over sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was chromatographed(ISCO, hexane/EtOAc, 0-40%, 40 min) to give yellow solids (0.55 g, 92%).¹H NMR (DMSO-d₆, 400 MHz): δ 7.73 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz,2H), 6.41 (s, 1H), 4.52 (s, 2H), 3.50 (t, J=8.0 Hz, 2H), 2.95 (t, J=8.0Hz, 2H), 2.20 (s, 3H), 2.11 (s, 3H).

The following compounds were prepared by the above procedure:

-   4,6-Dimethyl-5-nitro-1-(4-fluorobenzyl)-indoline-   4,6-Dimethyl-5-nitro-1-(3-chlorobenzyl)-indoline-   4,6-Dimethyl-5-nitro-1-(4-bromoobenzyl)-indoline-   4,6-Dimethyl-5-nitro-1-(3,4-difluorobenzyl)-indoline-   4,6-Dimethyl-5-nitro-1-(naphthalen-2-ylmethyl)-indoline-   4,6-Dimethyl-5-nitro-1-(pyridin-4-ylmethyl)-indoline-   4,6-Dimethyl-5-nitro-1-(pyridin-3-ylmethyl)-indoline

4,6-Dimethyl-5-nitro-1-(4-(trifluoromethyl)benzyl)-1H-indole (12): R═CF₃

A solution of 4,6-dimethyl-5-nitro-1-(4-trifluoromethyl-benzyl)-indoline(350 mg, 1 mmol) and DDQ (454 mg, 2 mmol) in 30 ml of anhydrous dioxanewas stirred a 50° C. for 2 days. After cooling, the solvent was removedunder reduced pressure and the residue was purified by silica gel columnchromatography (ISCO, hexane/EtOAc, 0-40%, 40 min) to give yellowcrystals (300 mg, 86%).

The following compounds were prepared by the above procedure.

-   4,6-Dimethyl-5-nitro-1-(4-fluorobenzyl)-1H-indole-   4,6-Dimethyl-5-nitro-1-(4-chlorobenzyl)-1H-indole-   4,6-Dimethyl-5-nitro-1-(4-bromobenzyl)-1H-indole-   4,6-Dimethyl-5-nitro-1-(3,4-difluorobenzyl)-1H-indole-   4,6-Dimethyl-5-nitro-1-(3,5-difluorobenzyl)-1H-indole

1-(4-Trifluoromethyl-benzyl)-4,6-dimethyl-5-aminoindoline (10): R═CF₃

1-(4-Trifluoromethyl-benzyl)-4,6-dimethyl-5-nitroindoline (1.0 g) wasdissolved in methanol (40 ml) and catalytic amount of Raney Ni was addedto allow hydrogenation at room temperature under regular pressure. Afterthe completion of the reaction, catalyst was filtered off, and thefiltrate was evaporated under reduced pressure to give the white solidproduct, which is pure enough for next step without furtherpurification.

The following compounds were prepared by the above procedure:

-   1-(4-Fluorobenzyl)-4,6-dimethyl-5-aminoindoline-   1-(3-Chlorobenzyl)-4,6-dimethyl-5-aminoindoline-   1-(4-Bromobenzyl)-4,6-dimethyl-5-aminoindoline-   1-(3,4-Difluorobenzyl)-4,6-dimethyl-5-aminoindoline-   1-(Naphthalen-2-ylmethyl)-4,6-dimethyl-5-aminoindoline-   1-(Pyridin-4-ylmethyl)-4,6-dimethyl-5-aminoindoline-   1-(Pyridin-3-ylmethyl)-4,6-dimethyl-5-aminoindoline-   4,6-Dimethyl-5-amino-1-(4-(trifluoromethyl)benzyl)-1H-indole-   4,6-Dimethyl-5-amino-1-(4-fluorobenzyl)-1H-indole-   4,6-Dimethyl-5-amino-1-(4-chlorobenzyl)-1H-indole-   4,6-Dimethyl-5-amino-1-(4-bromobenzyl)-1H-indole-   4,6-Dimethyl-5-amino-1-(3,4-difluorobenzyl)-1H-indole-   4,6-Dimethyl-5-amino-1-(3,5-difluorobenzyl)-1H-indole

N-[1-(4-Trifluoromethyl-benzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide(11): R═CF₃

To a solution of5-amino-4,6-dimethyl-1-(4-trifluoromethylbenzyl)indoline (0.26 g, 0.82mmol) from above and triethylamine (125 mg, 1.24 mmol) in anhydrousmethylene chloride (20 ml) was added dropwise tert-butyl acetyl chloride(135 mg, 1 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 18 hours. Water was added to the reaction mixture, andthe mixture was washed with saturated brine and dried over sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (ISCO, hexane/EtOAc,0-40%, 40 min) and recrystallized from hexane/EtOAc (5:1) to give 290 mg(85%) of the white solids. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.80 (brs, 1H,exchangeable with D₂O, NH), 7.72 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz,2H), 6.29 (s, 1H), 4.34 (s, 2H), 3.28 (t, J=8.0 Hz, 2H), 2.82 (t, J=8.0Hz, 2H), 2.17 (s, 2H), 2.03 (s, 3H), 1.96 (s, 3H), 1.07 (s, 9H). MS: 419(M+1).

The following compounds were prepared by the above procedure.

N-[1-(4-Fluorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.78 (brs, 1H, exchangeable with D₂O, NH),7.37 (dd, J=8.8 and 5.7 Hz, 2H), 7.16 (t, J=8.8 Hz, 2H), 6.32 (s, 1H),4.22 (s, 2H), 3.22 (t, J=8.0 Hz, 2H), 2.79 (t, J=8.0 Hz, 2H), 2.17 (s,2H), 2.03 (s, 3H), 1.95 (s, 3H), 1.05 (s, 9H). MS: 369 (M+1).

N-[1-(3-Chlorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.79 (brs, 1H, exchangeable with D₂O, NH),7.34 (m, 4H), 6.29 (s, 1H), 4.25 (s, 2H), 3.26 (t, J=8.0 Hz, 2H), 2.81(t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.03 (s, 3H), 1.96 (s, 3H), 1.05 (s,9H). MS: 385 (M+1).

N-[1-(4-Bromobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.78 (brs, 1H, exchangeable with D₂O, NH),7.54 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 6.29 (s, 1H), 4.21 (s,2H), 3.24 (t, J=8.0 Hz, 2H), 2.80 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.02(s, 3H), 1.95 (s, 3H), 1.05 (s, 9H). MS: 429 (M+1).

N-[1-(3,4-Difluorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.79 (brs, 1H, exchangeable with D₂O, NH),7.41 (m, 2H), 7.19 (m, 1H), 6.30 (s, 1H), 4.22 (s, 2H), 3.25 (t, J=8.0Hz, 2H), 2.80 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.03 (s, 3H), 1.96 (s,3H), 1.05 (s, 9H). MS: 387 (M+1).

N-(4,6-Dimethyl-1-(naphthalen-2-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.79 (brs, 1H, exchangeable with D₂O, NH),7.89 (m, 4H), 7.50 (m, 3H), 6.35 (s, 1H), 4.39 (s, 2H), 3.29 (t, J=8.0Hz, 2H), 2.84 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.03 (s, 3H), 1.97 (s,3H), 1.05 (s, 9H). MS: 401 (M+1).

N-(4,6-Dimethyl-1-(pyridin-4-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.80 (brs, 1H, exchangeable with D₂O, NH),8.52 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 6.25 (s, 1H), 4.28 (s,2H), 3.30 (t, J=8.0 Hz, 2H), 2.84 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.02(s, 3H), 1.97 (s, 3H), 1.05 (s, 9H). MS: 352 (M+1).

N-(4,6-Dimethyl-1-(pyridin-3-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.79 (brs, 1H, exchangeable with D₂O, NH),8.57 (d, J=2.0 Hz, 1H), 8.49 (dd, J=2.0 and 4.4 Hz, 1H), 7.74 (d, J=8.0Hz, 1H), 7.38 (dd, J=8.0 and 4.4 Hz, 1H), 6.36 (s, 1H), 4.27 (s, 2H),3.24 (t, J=8.0 Hz, 2H), 2.79 (t, J=8.0 Hz, 2H), 2.17 (s, 2H), 2.04 (s,3H), 1.95 (s, 3H), 1.05 (s, 9H). MS: 352 (M+1).

N-(4,6-Dimethyl-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide

¹H NMR (DMSO-d₆, 400 MHz): δ 9.00 (brs, 1H, exchangeable with D₂O, NH),7.67 (d, J=8.0 Hz, 2H), 7.41 (d, J=3.2 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H),7.09 (s, 1H), 6.50 (d, J=3.2 Hz, 1H), 5.50 (s, 2H), 2.29 (s, 2H), 2.22(s, 3H), 2.19 (s, 3H), 1.07 (s, 9H). MS: 417 (M+1).

N-(4,6-Dimethyl-1-(4-(fluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.99 (brs, 1H, exchangeable with D₂O, NH),7.39 (d, J=3.2 Hz, 1H), 7.21 (dd, J=8.8 and 5.7 Hz, 2H), 7.15 (t, J=8.8Hz, 2H), 7.12 (s, 1H), 6.46 (d, J=3.2 Hz, 1H), 5.36 (s, 2H), 2.28 (s,2H), 2.22 (s, 3H), 2.20 (s, 3H), 1.07 (s, 9H). MS: 367 (M+1).

N-(4,6-Dimethyl-1-(3,4-difluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide

¹H NMR (DMSO-d₆, 400 MHz): δ 9.00 (brs, 1H, exchangeable with D₂O, NH),7.41 (d, J=3.2 Hz, 1H), 7.35 (m, 1H), 7.23 (m, 1H), 7.14 (s, 1H), 6.95(m, 1H), 6.48 (d, J=3.2 Hz, 1H), 5.36 (s, 2H), 2.28 (s, 2H), 2.22 (s,3H), 2.20 (s, 3H), 1.07 (s, 9H). MS: 385 (M+1).

N-(4,6-Dimethyl-1-(3,5-difluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide

¹H NMR (DMSO-d₆, 400 MHz): δ 9.01 (brs, 1H, exchangeable with D₂O, NH),7.43 (d, J=3.2 Hz, 1H), 7.13 (s, 1H), 7.10 (m, 1H), 6.81 (m, 2H), 6.49(d, J=3.2 Hz, 1H), 5.40 (s, 2H), 2.29 (s, 2H), 2.22 (s, 3H), 2.21 (s,3H), 1.08 (s, 9H). MS: 385 (M+1).

N-(4,6-Dimethyl-1-(3-chlorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide

¹H NMR (DMSO-d₆, 400 MHz): δ 9.00 (brs, 1H, exchangeable with D₂O, NH),7.41 (d, J=3.2 Hz, 1H), 7.31 (m, 2H), 7.19 (s, 1H), 7.12 (s, 1H), 7.03(m, 1H), 6.95 (m, 1H), 6.49 (d, J=3.2 Hz, 1H), 5.39 (s, 2H), 2.29 (s,2H), 2.22 (s, 3H), 2.20 (s, 3H), 1.08 (s, 9H). MS: 383 (M+1).

N-(4,6-Dimethyl-1-(4-bromobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide

¹H NMR (DMSO-d₆, 400 MHz): δ 8.99 (brs, 1H, exchangeable with D₂O, NH),7.49 (d, J=8.4 Hz, 2H), 7.38 (d, J=3.2 Hz, 1H), 7.08 (s, 1H), 7.07 (d,J=8.4 Hz, 1H), 6.47 (d, J=3.2 Hz, 1H), 5.36 (s, 2H), 2.28 (s, 2H), 2.19(s, 3H), 2.17 (s, 3H), 1.07 (s, 9H). MS: 427 (M+1).

Biological Results

Compounds of this invention formula were evaluated as potassium channelmodulators by measuring rhubidium ion release in the following assay.

Methods: PC-12 cells were grown at 37° C. and 5% CO₂ in DMEM/F12 Mediumsupplemented with 10% horse serum, 5% fetal bovine serum, 2 mMglutamine, 100 U/ml penicillin, 100 U/ml streptomycin. They were platedin poly-D-lysine-coated 96-well cell culture microplates at a density of40,000 cells/well and differentiated with 100 ng/ml NGF-7s for 2-5 days.For the assay, the medium was aspirated and the cells were washed oncewith 0.2 ml in wash buffer (25 mM HEPES, pH 7.4, 150 mM NaCl, 1 mMMgCl₂, 0.8 mM NaH₂PO₄, 2 mM CaCl₂). The cells were then loaded with 0.2ml Rb⁺ loading buffer (wash buffer plus 5.4 mM RbCl₂, 5 mM glucose) andincubated at 37° C. for 2 h. Attached cells were quickly washed threetimes with buffer (same as Rb⁺ loading buffer, but containing 5.4 mM KClinstead of RbCl) to remove extracellular Rb⁺. Immediately following thewash, 0.2 ml of depolarization buffer (wash buffer plus 15 mM KCl) withor without compounds was added to the cells to activate efflux ofpotassium ion channels. After incubation for 10 min at room temperature,the supernatant was carefully removed and collected. Cells were lysed bythe addition of 0.2 ml of lysis buffer (depolarization buffer plus 0.1%Triton X-100) and the cell lysates were also collected. If collectedsamples were not immediately analyzed for Rb⁺ contents by atomicabsorption spectroscopy (see below), they were stored at 4° C. withoutany negative effects on subsequent Rb⁺ analysis.

The concentration of Rb⁺ in the supernatants (Rb⁺ _(Sup)) and celllysates (Rb⁺ _(Lys)) was quantified using an ICR8000 flame atomicabsorption spectrometer (Aurora Biomed Inc., Vancouver, B.C.) underconditions defined by the manufacturer. One 0.05 ml samples wereprocessed automatically from microtiter plates by dilution with an equalvolume of Rb⁺ sample analysis buffer and injection into an air-acetyleneflame. The amount of Rb⁺ in the sample was measured by absorption at 780nm using a hollow cathode lamp as light source and a PMT detector. Acalibration curve covering the range 0-5 mg/L Rb⁺ in sample analysisbuffer was generated with each set of plates. The percent Rb⁺ efflux (F)was defined by

F=[Rb⁺ _(Sup)/(Rb⁺ _(Sup)+Rb⁺ _(Lys))]×100%.

The effect (E) of a compound was defined by:

E=[(F _(c) −F _(b))/(F _(s) −F _(b))]×100%

where the F_(c) is the efflux in the presence of compound indepolarization buffer, F_(b) is the efflux in basal buffer, and F_(s) isthe efflux in depolarization buffer, and F_(c) is the efflux in thepresence of compound in depolarization buffer. The effect (E) andcompound concentration relationship was plotted to calculate an EC₅₀value, a compound's concentration for 50% of maximal Rb⁺ efflux. Theresults are shown below. Legend: A: EC50=1 nM-50 nM; B: EC50=50 nM-100nM; C: EC50=100 nM-200 nM; D: EC50=200 nM-500 nM.

TABLE 1 ACTIVITIES OF EXEMPLARY COMPOUNDS ACTIV- COMPOUND ITY

A

A

A

A

A

A

D

A

A

A

A

A

A

A

C

1. A compound of formula I

where the dashed line represents an optional double bond; where R₁ isphenyl, naphthyl, pyridyl, pyrimidyl, pyrrolyl, imidazolyl, pyrazyl,furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl,optionally substituted with one or two substituents selectedindependently from halogen, C₁-C₆ alkyl, mono-halo C₁-C₆ alkyl, di-haloC₁-C₆ alkyl, CF₃, CN, S—C₁-C₆ alkyl, or O—C₁-C₆ alkyl; R₂ is H, methyl,or halogen; R₃ and R₄ are, independently, CF₃, OCF₃, OC₁-C₃ alkyl, haloor C₁-C₃ alkyl, where the C₁-C₃ alkyl groups are optionally substitutedwith one or more halogen atoms; X═O or S; Y is O or S; q=1 or 0; R₅ isC₁-C₆ alkyl where the C₁-C₆ alkyl alkyl group is optionally substitutedwith one or two groups selected, independently, from OH, OMe, OEt, F,CF₃, Cl, or CN; (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆cycloalkyl, CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl,CH═CR₆—C₃-C₆ cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl,CH₂(CHR₆)_(w)C₅-C₆ cycloalkenyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ar₁,(CHR₆)_(w)Ar₁, CH₂(CHR₆)_(w)Ar₁, or (CHR₆)_(w)CH₂Ar₁, where w=0-3, Ar₁is phenyl, pyridyl, pyrrolyl, thienyl, or furyl, and R₆ is hydrogen,methyl, halogen, or methoxy; where all cyclic groups are optionallysubstituted with one or two substituents selected independently fromC₁-C₃ alkyl, halogen, OH, OMe, SMe, CN, CH₂F, and trifluoromethyl; or apharmaceutically acceptable salt, ester, or hydrate thereof.
 2. Thecompound of claim 1, where R₁ is phenyl, naphthyl, pyrimidyl, optionallysubstituted with one or two substituents selected independently fromhalogen, C₁-C₄ alkyl, mono-halo C₁-C₃ alkyl, CF₃, CN, S—CH₃, or O—C₁-C₃alkyl; or R₁ is pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl,thiazolyl, or isothiazolyl, optionally substituted with halogen,halomethyl, or C₁-C₄ alkyl; R₂ is H, methyl, or halogen; R₅ is C₃-C₆alkyl, (CHR₆)_(w)C₃-C₆ cycloalkyl, (CHR₆)_(w)CH₂C₃-C₆ cycloalkyl,CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl, CR₆═CH—C₃-C₆ cycloalkyl, CH═CR₆—C₃-C₆cycloalkyl, (CHR₆)_(w)C₅-C₆ cycloalkenyl, CH₂(CHR₆)_(w)C₅-C₆cycloalkenyl, C₂-C₆ alkenyl, Ar₁, (CHR₆)_(w)Ar₁, CH₂(CHR₆)_(w)Ar₁, whereR₆ is H or methyl; where w is 1 or 2; and where the C₃-C₆ alkyl group isoptionally substituted with one F or Cl.
 3. The compound of claim 2where R₁ is phenyl, naphthyl, or pyridyl, optionally substituted withone substituent chosen from methyl, ethyl, halomethyl, halogen, cyano,SCH₃, methoxy, and CF₃ and optionally further substituted with halogenor methyl; or R₁ is thienyl, oxazolyl, or isothiazolyl, optionallysubstituted with halogen or C₁-C₄ alkyl; R₂ is H; R₃ and R₄ are,independently, Cl, CH₃, or methoxy; and R₅ is C₃-C₆ alkyl,(CHR₆)_(w)C₃-C₆ cycloalkyl, CH₂(CHR₆)_(w)C₃-C₆ cycloalkyl, CR₆═CH—C₃-C₆cycloalkyl, CH═CR₆—C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, Ar₁, (CHR₆)_(w)Ar₁,or CH₂(CHR₆)_(w)Ar₁.
 4. The compound of claim 3, where R₁ is para-halophenyl or difluorophenyl.
 5. The compound of claim 3, where R₁ issubstituted with methyl or trifluoromethyl.
 6. The compound of any ofclaim 3, 4, or 5, where X is S.
 7. The compound of claim 2, which is acompound of formula IA


8. The compound of claim 2, which is a compound of formula IB


9. The compound of claim 2, which is a compound of formula IC


10. The compound of claim 2, which is a compound of formula ID


11. The compound of any of claim 7, 8, 9, or 10, where R₃ and R₄ are,independently, methyl, chloro, or methoxy.
 12. The compound of any ofclaim 6, 7, 8, 9, or 10, where R₂ is H and R₃ and R₄ are both methyl.13. The compound of any of claim 7, 8, 9, or 10, where R₃ and R₄ areboth methyl; R₁ is phenyl, naphthyl, or pyridyl, optionally substitutedwith halogen or trifluoromethyl; and R₅ is C₅-C₆ alkyl.
 14. Acomposition comprising a compound of formula I according to claim 1 anda pharmaceutically acceptable carrier.
 15. A composition comprising apharmaceutically acceptable carrier and one or more of the following: acompound of formula I according to claim 1, a pharmaceuticallyacceptable salt of a compound of formula I, a pharmaceuticallyacceptable ester of a compound of formula I and a pharmaceuticallyacceptable solvate of a compound of formula I.
 16. (canceled)
 17. Thecompound of claim 7, where R₃ and R₄ are both methyl, and R₅ is C₅-C₆alkyl.
 18. The compound of claim 17, where R₁ is mono-substitutedphenyl.
 19. The compound of claim 18, where R₁ is para fluoro phenyl orpara trifluoromethyl phenyl.
 20. The compound of claim 17, where R₁ is3,5-difluorophenyl or 3-fluorophenyl.
 21. The compound of claim 9, whereR₃ and R₄ are both methyl, and R₅ is C₅-C₆ alkyl.
 22. The compound ofclaim 21, where R₁ is pyridyl or phenyl, optionally substituted with oneadditional substituent.
 23. The compound of claim 22, where R₁ is parafluoro phenyl or para trifluoromethyl phenyl.
 24. The compound of claim21, where R₁ is 3,5-difluorophenyl or 3-fluorophenyl.
 25. A compositioncomprising a compound according to claim 7 and a pharmaceuticallyacceptable carrier.
 26. A composition comprising one or more of thefollowing: a compound of formula IA according to claim 7; apharmaceutically acceptable salt of a compound of formula IA; apharmaceutically acceptable solvate of a compound of formula IA; apharmaceutically acceptable ester of a compound of formula IA. 27.(canceled)
 28. A composition comprising a compound according to claim 9and a pharmaceutically acceptable carrier.
 29. A composition comprisingone or more of the following: a compound of formula IC according toclaim 1; a salt of a compound of formula IC; a pharmaceuticallyacceptable salt of a compound of formula IC; a pharmaceuticallyacceptable ester of a compound of formula IC; a pharmaceuticallyacceptable solvate of a compound of formula IC. 30.-31. (canceled)
 32. Acomposition comprising a pharmaceutically acceptable carrier and eithera compound chosen from one of the following or a pharmaceuticallyacceptable salt, solvate, or ester thereof:N-[1-(4-Trifluoromethylbenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramideN-[1-(4-Fluorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramideN-[1-(3-Chlorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramideN-[1-(4-Bromobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramideN-[1-(3,4-Difluorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramideN-(4,6-Dimethyl-1-(naphthalen-2-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamideN-(4,6-Dimethyl-1-(pyridin-4-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamideN-(4,6-Dimethyl-1-(pyridin-3-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamideN-(4,6-Dimethyl-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)-3,3-dimethylbutanamideN-(4,6-Dimethyl-1-(4-(fluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamideN-(4,6-Dimethyl-1-(3,4-difluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamideN-(4,6-Dimethyl-1-(3,5-difluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamideN-(4,6-Dimethyl-1-(3-chlorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamideandN-(4,6-Dimethyl-1-(4-bromobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide.33. (canceled)